This is an application for a K08 award for Dr. Mark McCauley, a cardiologist and cardiac electrophysiologist at Baylor College of Medicine, Houston. Dr. McCauley is establishing himself as a young investigator in clinical and translational research of cardiac arrhythmias. This K08 award will provide Dr. McCauley with the support necessary to accomplish the following goals: 1) to become an expert at the cellular mechanisms of atrial fibrillation (AF); 2) to conduct basic and translational research of the biophysical aspects of AF initiation and maintenance; 3) to implement advanced molecular, genetic, and cellular imaging techniques in studies of human and murine tissues prone to AF; 4) to identify key molecular interactions responsible for atrial stunning in AF; 5) to develop an independent translational research career. To achieve these goals, Dr. McCauley has assembled a mentoring team composed of a primary mentor, Dr. Xander Wehrens, Director of the Cardiovascular Research Institute at Baylor College of Medicine, who conducts basic science research in the mechanisms of cardiac arrhythmias and heart failure, and two collaborating investigators: Dr. James Martin, a scientist who examines the role of genetics in cardiovascular development, and Dr. Na Li, a scientist who examines the role of Ca2+ signaling in AF. AF is a significant contributor to risk of stroke, which is the #5 cause of death in the United States. Long-standing AF leads to atrial stunning, which contributes to stroke in AF. Dr. McCauley's research will focus on the molecular determinants of atrial hypocontractility in AF, with an emphasis on protein phosphatase 1 (PP1), a key regulator of sarcomeric Ca2+ sensitivity and cardiac contractility. Dr. McCauley will determine how PP1 protein subunit interactions affect sarcomere phosphorylation (Aim 1), affect Ca2+ sensitivity and cardiac contractility (Aim 2), and how reversal of pathologic PP1 signaling may improve cardiac contractility in AF (Aim 3). More specifically, in Aim 1, Dr. McCauley will examine PP1 expression, subunit binding, and sarcomere phosphorylation in both human AF tissue (atrial appendage) and in murine atrial cells in vitro. In Aim 2, he will use Ca2+ imaging and advanced microscopy techniques to examine how alterations in PP1 expression and binding contribute to Ca2+ sensitivity and cardiac contractility. In Aim 3, he will experimentally modulate regulatory and catalytic PP1 subunit binding in a proven murine AF model to modulate atrial contractility. By examining this important molecular interaction implicated in atrial stunning, Dr. McCauley will seek to determine an important mechanism leading to stroke risk in AF. This research will form the basis for a targeted treatment for AF-mediated hypocontractility, which will form the rationale and preliminary data for an R01 grant application before the end of the K award.